The central executive network moderates the relationship between posttraumatic stress symptom severity and gastrointestinal related issues

Although most adults experience at least one traumatic event in their lifetime, a smaller proportion will go on to be clinically diagnosed with post-traumatic stress disorder (PTSD). Persons diagnosed with PTSD have a greater likelihood of developing gastrointestinal (GI) disorders. However, the extent to which subclinical levels of post-traumatic stress (PTS) correspond with the incidence of GI issues in a normative sample is unclear. Resting state fMRI, medical history, psychological survey, and anthropometric data were acquired from the Enhanced Nathan Kline Institute-Rockland Sample (n = 378; age range 18–85.6 years). The primary aim of this study was to test the main effect of subclinical PTS symptom severity on the number of endorsed GI issues. The secondary aim was to test the moderating effect of high versus low resting state functional connectivity (rsFC) of the central executive network (CEN) on the relationship between PTS symptom severity and GI issues. Trauma Symptom Checklist-40 (TSC-40) scores were positively associated with the number of endorsed GI issues (b = −0.038, SE = .009, p < .001). The interaction between TSC-40 scores and rsFC within the CEN was significant on GI issues after controlling for sociodemographic and cardiometabolic variables (b = −0.031, SE = .016, p < .05), such that above average rsFC within the CEN buffered the effect of TSC-40 scores on GI issues. Our findings of higher rsFC within the CEN moderating the magnitude of coincidence in PTS and GI symptom severity may reflect the mitigating role of executive control processes in the putative stress signaling mechanisms that contribute to gut dysbiosis.

guarantee participant anonymity.The data sharing protocol employed the removal of all potential HIPAA identifiers and the anonymization of facial features from anatomical images.Furthermore, this study adhered to a data use agreement of the Enhanced NKI-RS's data-sharing policy.
Data collection involved a semi-structured diagnostic psychiatric interview, a battery of psychiatric, cognitive, and behavioral assessments, and a multimodal brain imaging session described in previous studies 33 .Individuals with complete demographic, psychophysiological, rs-fMRI, and behavioral data were included in the analysis.Exclusionary criteria were based on a standardized clinical intake.They included a history of epilepsy, major depression, bipolar disorder, Alzheimer's dementia, Huntington's disease, meningitis, Parkinson's disease, schizophrenia, general anxiety, and loss of consciousness following head injury.Furthermore, individuals with a previous or current diagnosis of PTSD (as determined via semi-structured diagnostic interviews) or any eating disorders were excluded from our analyses due to their confounding effects on GI function 34,35 .Participants were asked to report if they were ever diagnosed with, IBS, Crohn's disease, UC, gastric reflux, and/or stomach/intestinal ulcers.In addition, participants were asked to self-report if they had experienced GI issues more generally.Those who endorsed general GI issues are reflected in the "stomach/intestinal problems" category in Table 1.

Measures
Symptoms related to stress and traumatic experiences were measured using the TSC-40.This scale was designed for the measurement of post-traumatic symptomatology associated with childhood trauma.The TSC-40 is a selfreported scale containing 40 items with six subscales: dissociation, anxiety, depression, a sexual abuse trauma index, sexual problems, and sleep disturbances 11 .Higher total TSC-40 scores signify higher trauma symptom severity.Construct validation for the total TSC-40 scale suggests that the scale demonstrates strong measurement invariance across participants with or without abuse-related and multiple trauma histories 36 .The TSC-40 has been used to assess PTS in several non-clinical samples 3711 .Cronbach's alpha of the TSC-40 for the entire cohort was high, α = 0.898.Additionally, studies using the TSC-40 indicate that it is a relatively reliable measure (subscale alphas typically range from 0.66 to 0.77, with alphas for the full-scale averaging between 0.89 and 0.91) 38 .

Cardiometabolic Variables
Body Mass Index (BMI) was calculated using reports of height (meters) and weight (kilograms) using the following formula: BMI = weight (kg)/height 2 (m 2 ).A complete metabolic panel was performed on fasting whole blood and included total serum cholesterol with a reference range for total serum cholesterol of 144-199 mg/dL.High-density lipoprotein (HDL) was also measured within a reference range of 35-70 mg/dL.The plasma lipid www.nature.com/scientificreports/concentration of triglycerides was also measured using a blood assay.The reference range for triglycerides was 0-199 mg/dL.Hematocrit was measured within a reference range of 14.0-18.0g/dL and 42-52%, respectively.

Neuroimaging
Acquisition A 3.0-T Siemens MAGNETOM Trio-Tim scanner was used to collect resting state scans using the following imaging parameters: TR = 1400 ms, TE = 30 ms, slice thickness = 3.0 mm, flip angle = 65°, field of view = 224 mm, slices = 64, and voxel size = 2.0 × 2.0 × 2.0 mm.Each participant's acquisition time was 10 min using a multi-band imaging sequence.The subjects were instructed to lay still inside the scanner with their eyes open and were asked not to fall asleep.High-resolution anatomical images (MPRAGE) were acquired using the following scanning parameters: TR = 1900 ms, TE = 2.52 ms, slice thickness = 1.0 mm, flip angle = 9°, field of view = 256 mm, and voxel size = 1.0 × 1.0 × 1.0 mm.All fMRI data used in the analysis are part of the NKI Enhanced dataset made publicly available by the international neuroimaging data sharing initiative 33 .During their brain scanning session, physiological and resting state fMRI data were specifically collected and analyzed from the 1400 ms TR resting state session.

Resting state functional connectivity analyses
We defined CEN regions of interest (ROIs) with a publicly available atlas 43 .For each of the CEN's 10 ROIs 43 , we placed a 5-mm sphere around peak activation coordinates for each discrete cluster within the left-and righthemisphere masks.Time-series data for each voxel were demeaned and converted to percent signal change scores to reduce variability between adults.We then calculated the ROI seed data as the average percent signal change for all voxels in each region.The rsFC was quantified as the Pearson correlation (r) relating the average time series in each ROI with the average time series in all other ROIs within the network.After converting these r values into Z-scores using Fisher's transformation, we averaged all pairwise Z-scores within the network to form a summary statistic, reflecting the mean connectivity between all nodes within the CEN.We then performed a mean split of the average within-network rsFC of the CEN to form a group of high and low CEN rsFC, to test between-group factors as a main interaction effect in the model.

Statistical analysis
The current analysis investigates the relationship between TSC-40 scores (independent variable), rsFC within the CEN (moderator), and GI burden (dependent variable).The primary objective is to determine if TSC-40 scores predict the number of endorsed GI-related issues and further explore the interaction between CEN connectivity and TSC-40 scores.In the primary model, raw summative TSC-40 scores were used.CEN connectivity is dummy coded (0 = low CEN connectivity, 1 = high CEN connectivity) based upon median split, and the number of endorsed GI-related issues was measured as count data.
Poisson regression models were specified with the primary study variables to assess their impact on the relationship between TSC-40 on GI burden as a function of CEN rsFC, given the count nature of the dependent variable.Subsequentially a secondary model was constructed to adjust for the potential demographic and cardiometabolic confounding effects.Researchers made a deliberate choice to incorporate cardiometabolic variables-specifically glucose, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)-as covariates to mitigate potential confounding influences on the interplay between GI burden, TSC-40 scores, and resting-state functional connectivity (rsFC) within the Central Executive Network (CEN).This preemptive inclusion was guided by the known impact of metabolic health on neurocognitive functions 44,45 and stress responses 46 , which are critical elements within the scope of our study.
Because of the potentially confounding effects of overlap in indicators of cardiometabolic status in the secondary model, multicollinearity will be rigorously assessed using the Variance Inflation Factor (VIF).A VIF threshold of 5 will be employed to indicate significant multicollinearity among the covariates.Should any of the covariates exhibit a VIF value equal to or exceeding this threshold, it will indicate a high degree of collinearity, which may necessitate further action.Possible steps to address identified multicollinearity agreed upon in the literature include examining for redundant variables, considering the removal or consolidation of highly collinear variables, or applying advanced statistical methods such as ridge regression.These approaches are intended to ensure that the model's validity is not compromised by interdependencies among the predictors and that the interpretations of the regression coefficients remain reliable and meaningful.If necessary, overdispersion in the Poisson model will be checked, and a negative binomial regression will be considered.Assumptions of linearity, independence, and homoscedasticity will be verified.All analyses were conducted using R (R core Team, 2023) and various packages including dplyr 47 , psych 48 , ggplot 49 , and caret 50   (20.52± 12.45).In terms of racial composition, the percentage of individuals identified as Black was significantly higher in the high CEN group (24.43%) compared to the low CEN group (14.36%).Furthermore, the proportion of individuals diagnosed with IBS was higher in the low (13.86%) compared to the high CEN group (7.39%).Due to the dependent variable being count data, a Poisson regression was used to test the relationship between TSC-40 scores on the total number of endorsed gastrointestinal burden as a function of rsFC within the CEN.
To examine the differential contributions of CEN group status (i.e., above or below rsFC within the CEN) on the relationship between TSC-40 on GI burden count, our adjusted model accounted for the following covariates: age, race, glucose, cholesterol, triglycerides, HDL, LDL, and hematocrit.In the unadjusted model, TSC-40 was positively associated with GI burden, b = −0.038,SE = 0.009, p < 0.001.Although there was no main effect for CEN group on GI burden count, the interaction term trended towards significance, b = −0.031,SE = 0.016, p 0.051.When controlling for covariates in the adjusted model, there is a main effect for CEN group (b = 0.659, SE = 0.278, p = 0.018), and the interaction term is significant (b = −0.030,SE = 0.010, p = 0.003) (Fig. 1).Among the listed covariates in the adjusted model, age (b = 0.022, SE = 0.004, p < 0.001) and race (b = 0.277, SE = 0.093, p = 0.003) were the only statistically significant covariates in the revised model (see Table 2).Post-hoc analysis using dummy coding for race and Black individuals as the reference group revealed that White individuals were more likely to endorse GI burden (b = 0.717, SE = 0.216, p < 0.001).This was the only racial group to significantly differ from the reference group.

Discussion
This study aimed to test the assumption that PTS symptom severity is associated with GI issues and that rsFC within the CEN moderates the association between TSC-40 scores and total GI issues that are endorsed in the absence of a PTSD diagnosis.Consistent with previous literature, we observed a positive correlation between TSC-40 scores and the number of GI issues reported after controlling for demographic and cardiometabolic factors.In line with our prediction, this effect was moderated by rsFC within the CEN.That is, in individuals with above-average connectivity within the CEN, there was a significantly smaller effect of PTS symptoms on the number of endorsed GI disorders compared to those with below-average connectivity of that network.These findings suggest that synchronic activation of nodes within the CEN may support neurological processes that moderate the known effect of traumatic stress on downstream signaling pathways.
Previous work examines the effects of clinical PTSD on GI issues [16][17][18] and implicates the CEN in PTSD and GI issues 31,32 .Our findings suggest that neurological mediating effects within the CEN on the relationship between PTS symptoms and the amount of endorsed GI-related issues can be observed in the absence of a clinical PTSD diagnosis.This highlights the need for a better understanding of the role of the CNS in the putative mechanisms linking traumatic stress exposure to the development of gastrointestinal disturbances in the context of executive functioning.One such plausible neurobiological mechanism that has gained traction in recent years is the effect of the sympathoadrenal response on GI dysbiosis 18 .The sympathoadrenal system allows for the sympathetic nervous system to elicit whole-body responses to stress via the adrenal medulla stimulation.Given the role of norepinephrine (NE) as a neuroendocrine molecule that interfaces central, autonomic, and enteric nervous systems, interest in the modulatory role of this neuroendocrine molecule in neuroimmune signaling in PTSD has risen.A recent meta-analysis of over 27 studies of combat and non-combat-related PTSD revealed significantly elevated levels of NE, but not cortisol or epinephrine when compared to non-traumatized controls 51 .As alluded to, the support for elevated NE in persons experiencing PTS dovetails with the current zeitgeist surrounding the stress-diathesis model of gut-brain axis interactions, wherein increased adrenergic signaling precipitates gut pathogenesis, including cell-mediated inflammation, altered gut motility and permeability, and proliferation of non-commensal gut flora 1, [52][53][54][55] .
Given the robust association between stress-related NE efflux and gut dysbiosis, our findings beg the question of exactly how rsFC of the CEN may mitigate NE expression in the process.Several research groups have turned their attention to the locus coeruleus (LC) as a potential target for neuroimmune signaling implicated in the pathophysiology of PTS.As the primary producer of NE, neurons within this small region of the brainstem influence the arousal state 56,57 .The CEN maintains inhibitory and excitatory control over the arousal state through projections to the NE neurons in the LC 58 .In a recent study, stress-related LC activity resulting from a serial response inhibition task was mediated by functional connectivity within prefrontal regions, namely the inferior frontal gyrus 55 .More sophisticated task-based research paradigms are required to determine whether synchrony within the CEN during real-time exposure to stress mitigates LC activity and downstream objective markers of gut dysbiosis.
Although this study focused on how rsFC within the CEN moderates the relationship between PTS and GI issues, additional psycho-neuro-immune research is needed to determine whether this mechanism extends to other allostatic disease processes.For example, a longitudinal study comparing two-year changes in CEN connectivity among children exposed to neighborhood violence found that higher rsFC of the CEN mitigated the effect of stress exposure on lipopolysaccharide-stimulated peripheral blood mononuclear cell expression of proinflammatory cytokines 59 .Given that gut dysbiosis shares pathophysiological pathways and is associated with a myriad of poor health outcomes, including increased susceptibility to infections 60 , cardiovascular disease and obesity 61 , certain cancers 62 , and psychiatric disorders [63][64][65] , more work is needed to understand how the organization of the CEN may protect against or exacerbate stress-related diseases.
Previous literature has also shown that psychosocial stress plays a role in certain GI disorders 66 .Racially/ ethnically minoritized groups are known to encounter more psychosocial challenges in their daily lives than their non-minoritized counterparts 67 .In our adjusted model, we used race as a covariate for GI count and found that White individuals were significantly more likely to endorse GI issues than Black individuals.This is in line with other literature that analyzed the prevalence of self-reported GI issues in the context of race.However, less is known about the underlying reasons for the disparities in self-reported GI issues.More research must assess if such discrepancies are due to underreporting, access, resilience, or a difference in GI-related disease prevalence.

Limitations and future directions
Despite the compelling findings of this study, it is important to acknowledge several limitations that might impact the generalizability and interpretation of our results.
Firstly, the sample lacks ethnic diversity.The sample's composition was predominantly white and notably excluded Hispanic individuals.The demographics of this study present a limitation in reflecting the full spectrum www.nature.com/scientificreports/ of racial and ethnic experiences, particularly given the documented disparities in health outcomes, including PTSD 68 , GI issues 69 , and brain connectivity 70 across different ethnic groups.The over-representation of white participants risks biasing the results towards their experiences, potentially obscuring critical variations in how different racial and ethnic groups experience or express the phenomena within this study.Such limitations not only narrow our understanding but may also perpetuate existing health disparities by failing to adequately capture and analyze the unique health profiles and social experiences of more diverse populations.Future research must strive for greater racial and ethnic diversity, including refined categorizations of race/ethnicity (e.g., Middle Eastern/North Africans are often conflated as White) to broaden the applicability and enrich the relevance of the findings.Secondly, the incidence of GI issues in this sample was based on self-report.Moreover, information on the history, duration, and severity of GI diagnoses endorsed was not collected or verified.Future models should be able to account for GI disease history as potential moderators of the observed relationships.Such information can further help to elucidate the pathophysiological mechanisms involved in stress-related GI disease processes.
Finally, this study was cross-sectional in nature, and the gut-brain axis is a well-documented bidirectional pathway, further limiting causal inferences drawn regarding the effect of PTS on GI issues.This design restricted our ability to establish temporal precedence, a crucial element for causal claims.Without establishing temporal precedence our data may also speak to the contribution of GI disease comorbidity to the exacerbation of PTS symptom severity.Future longitudinal investigations may help to determine whether the incidence of GI disease or connectivity within the CEN predicts the progression of PTS to a clinical diagnosis of PTSD.
A potential future direction of research is through PTSD treatments in trauma-exposed subclinical populations, as empirical evidence supports the plasticity of the rsFC as a potential therapeutic mechanism.For example, cognitive processing therapy (CPT) was found to normalize CEN connectivity following 12 sessions of treatment within a cohort of traumatized women 71 .Furthermore, CPT increased global connectivity in the CEN in veterans with PTSD 72 .Cognitive behavioral therapy has also demonstrated similar results for PTSD, with 12 weeks of manualized sessions significantly increasing intrinsic functional connectivity between the amygdala and regions within the CEN 73 .Another cognitive-oriented therapy (mindfulness-based exposure therapy) has similarly resulted in an increase in connectivity between prefrontal structures, along with reductions in avoidance and hyperarousal symptomology, among veterans with PTSD 74 .Given this evidence across an array of therapeutic approaches, it appears that CEN connectivity covaries as a function of trauma symptom severity and, therefore, may mitigate the extent to which the processing of trauma-related stressors impacts physiological arousal and its outcomes.While we were not privy to the types of traumatic events experienced by participants or when that experience took place, these are important characteristics that should be considered in future work as they might mitigate therapeutic effects.
Nonetheless, there is parallel evidence supporting the impact of cognitive emotion regulation strategies on gastrointestinal complaints is robust [75][76][77][78] .A systematic review on the efficacy of cognitive behavioral therapy for IBS demonstrated that it is moderately effective across various formats of administration, and the benefits are sustained through long-term follow-up 79 .Interestingly, a randomized controlled trial implementing this form of therapy for persons with IBS demonstrated improvements in GI symptomology, independent of its effects on psychological distress 77 .

Conclusion
To our knowledge, this is the first paper to directly assess the extent to which CEN connectivity moderates the relationship between trauma symptom severity and GI issues in a non-clinical PTSD sample.Moving forward understanding the underlying gut-brain axis mechanisms may not only deepen our insights into the role of frontal lobe functioning in buffering stress-related GI diseases but also pave the way for novel therapeutic interventions.Moreover, this and other investigations support the use of cognitive and behavioral strategies to address post-traumatic stress-related GI issues, by enhancing functional connectivity of brain regions supporting executive functioning.Thus, it is imperative to foster an integrated approach to bridging the gap between neuroscience, psychology, and gastroenterology in order to facilitate mental and physical well-being.

Figure 1 .
Figure 1.Endorsed gastrointestinal (GI) issue count and trauma symptom severity by central executive network (CEN) connectivity group.CEN connectivity (low vs. high) was found to be a moderator for the relationship between trauma symptom severity measured by the Trauma Symptom Severity Checklist (TSC-40) and the number of endorsed gastrointestinal issues (e.g., Irritable Bowel Syndrome, Chron's Disease, Stomach/ intestinal ulcers, general stomach/intestinal problems).

Table 1 .
Comparison of demographics by CEN Group Status.
a Mann-Whitney U Test was utilized for nonparametric comparisons of categorical data.*p < .05.Low CEN

rsFC (n = 202) High CEN rsFC (n = 176) T-statistic
ResultsA total of 378 individuals (ages 18-85.6 years, 64% female) with usable fMRI, behavioral, and self-report medical history data met the study inclusion criteria.A detailed comparison of demographics and medical history of persons in the low and high CEN connectivity groups is summarized in Table1.Medical history encompassed a broad range of indicators of gastrointestinal and cardiometabolic disease.Notable differences were observed in age, with the low CEN group being older on average (51.47 ± 17.20) compared to the high CEN group(45.62±18.39).TSC-40 scores, which reflect traumatic stress symptoms, were lower in the high CEN group(17.36±12.44)than in the low CEN group . Vol.:(0123456789) Scientific Reports | (2024) 14:10695 | https://doi.org/10.1038/s41598-024-61418-3www.nature.com/scientificreports/

Table 2 .
Regression table of the GI complain count model with or without covariates.CI = confidence interval.Unadjusted model includes the neurological and psychological variables of interest and the interaction of the two variables.The adjusted model includes age, race, glucose, triglyceride, HDL, and LDL.*p < .05.